The dipeptide L-alanyl-L-proline is a known chemical intermediate useful in the preparation of various pharmaceutical agents having enzyme inhibiting properties. Angiotensin converting enzyme for example is a carboxyl terminal dipeptidyl exopeptidase [E.C. 3.4.15.1] which converts angiotensin I into angiotensin II, a potent vasoconstrictor. Numerous compounds have been described which reduce blood pressure in humans by inhibiting the renin-angiotensin system (generally referred to as angiotensin converting enzyme inhibitors or simply ACE inhibitors).
Many of these synthetic ACE inhibitors have a dipeptide or tripeptide-type structure, typically but not invariable including an alanine component bound through its carboxy group to a nitrogen containing heterocyclic group in which a carboxy group is in the .alpha.-position to the nitrogen atom of the heterocyclic group. Two examples of such compounds are enalapril, which is N.sup.2 -[(S)-1-ethoxycarbonyl-3-phenyl-propyl]-L-alanyl-L-proline, and enalaprilat, which is N.sup.2 -[(S)-1-carboxy-3-phenylpropyl]-L-alanyl-L-proline.
In one reported synthesis of enalapril, L-alanyl-L-proline is coupled with an alkyl ester of 2-oxo-4-phenyl-butyrate; see Blacklock et al., J. Org. Chem. 3, 836-841 (1988). L-Alanyl-L-proline contains two chiral centers and a third chiral center is generated in this condensation. Although the condensation is reported to provide high diastereoselectivity, the ratio of the desired SSS diastereoisomer to the unwanted RSS diastereoisomer is reported to be 87:13.
The classical dipeptide synthesis in which the two amino acids in the form of protected derivatives are coupled and the two protecting groups are then removed also has been used in the preparation of L-alanyl-L-proline. For example, N-(t-butoxycarbonyl)-L-alanine can be coupled with the benzyl ester of L-proline in the presence of dicyclohexylcarbodiimide and the resulting benzyl ester of N-(t-butoxycarbonyl)-L-alanyl-L-proline treated with trifluoroacetic acid to remove the N-(t-butoxycarbonyl) group. Hydrolysis to cleave the benzyl ester then yields L-alanyl-L-proline. See Kleemann et al., Pharmazeutische Wirkstoffe, 1154 (1987).
Blacklock et al., supra, describe the preparation of L-alanyl-L-proline through the reaction of the unprotected proline (as the potassium salt) with a cyclic L-alanine N-carboxyanhydride, a 2,6-dioxo-4-substituted oxazolidine formed by the reaction of L-alanine and phosgene. While this so-called NCA chemistry offers many advantages, it requires the use of phosgene and careful control of the reactants during the course of the reaction.
Mukaiyama et al., Chemistry Letters, 1992, pages 181-184, describe the stereoselective preparation of various dipeptides through the reduction of 2-hydroxyimino amides with the lanthanide samarium diiodide.